Non-acute oncogenic retroviruses cause tumors in vivo by inserting next to cellular oncogenes and activating their expression. Because this event is stochastic, the higher the virus levels within an animal, the more likely it is that oncogenic transformation will occur. Since survival of viruses within animals is dependent on their ability to replicate and spread, most viruses have evolved a variety of mechanisms that not only enhance replication, but allow them to escape immune detection. In this Program, it is our goal to use two retroviruses, MMTV and Gross MLV (G-MLV), as model systems for the study of the mechanisms that oncogenic viruses use to achieve viremia and transformation. Overall, we will determine the relationship between the cell types that these viruses infection, how virus spreads between different cells, and how viruses that infect lymphocytes avoid immune detection and elimination. To accomplish this, three projects are proposed. project 1 (Susan Ross, Project Leader) will study how MMTV-infected lymphocytes spread virus, leading to mammary cell infection and tumorigenesis. In collaboration with Project 2 (Jaquelin Dudley, Project Leader), the mammary tumor-causing MMTV will be compared to a T lymphoma-inducing variant of MMTV, TBLV, with respect to which cell types are infected. The role of immune system avoidance in the spread of MMTV will also be studied in collaboration with Project 3 (Glen Gaulton, Project Leader). Project 2 will delineate the transcriptional regulatory elements within the TBLV long terminal repeat that alter its cell type tropism from mammary to T cells, the roles of the truncation of the MMTV superantigen and of pro-viral insertion into the c-myc oncogene protein in transformation. Project 3 will study the tissue- specific tropism of the T lymphoma-inducing virus, G-MLV, which induces immune tolerance by infection of thymic medullary epithelia. The role of gene expression in thymic medullary epithelia and how immune tolerance is induced will also be addressed in Project 3. These Projects will be supported by three Cores (Administrative, Mouse Breeding/Transgenic and Virus Vector). Thus, our studies will lead to a better understanding of the multiple mechanisms used by oncogenic retrovirus to infect and ultimately cause cancer within their host.